Bipolar Spectrum

Journal of Affective Disorders 59 (2000) S5S30
www.elsevier.com / locate / jad
Review article
Re-evaluating the prevalence of and diagnostic composition within

the broad clinical spectrum of bipolar disorders
a,
Hagop S. Akiskal *, Marc L. Bourgeois , Jules Angst , Robert Post ,
e , Robert Hirschfeld f
Hans-Jurgen
Moller
a
International Mood Center, University of California at San Diego, La Jolla, CA, USA
b
University of Bordeaux, France
c
Zurich University Psychiatric Hospital, Switzerland
d
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, USA
e
Psychiatric Hospital of the University of Munich, Germany
f
Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, USA
Received 19 November 1999; accepted 15 February 2000
Abstract
Until recently it was believed that no more than 1% of the general population has bipolar disorder. Emerging transatlantic
data are beginning to provide converging evidence for a higher prevalence of up to at least 5%. Manic states, even those with
mood-incongruent features, as well as mixed (dysphoric) mania, are now formally included in both ICD-10 and DSM-IV.
Mixed states occur in an average of 40% of bipolar patients over a lifetime; current evidence supports a broader definition of
mixed states consisting of full-blown mania with two or more concomitant depressive symptoms. The largest increase in
prevalence rates, however, is accounted for by softer clinical expressions of bipolarity situated between the extremes of
full-blown bipolar disorder where the person has at least one manic episode (bipolar I) and strictly defined unipolar major
depressive disorder without personal or family history for excited periods. Bipolar II is the prototype for these intermediary
conditions with major depressions and history of spontaneous hypomanic episodes; current evidence indicates that most
hypomanias pursue a recurrent course and that their usual duration is 13 days, falling below the arbitrary 4-day cutoff
required in DSM-IV. Depressions with antidepressant-associated hypomania (sometimes referred to as bipolar III) also
appear, on the basis of extensive international research neglected by both ICD-10 and DSM-IV, to belong to the clinical
spectrum of bipolar disorders. Broadly defined, the bipolar spectrum in studies conducted during the last decade accounts for
3055% of all major depressions. Rapid-cycling, defined as alternation of depressive and excited (at least four per year),
more often arise from a bipolar II than a bipolar I baseline; such cycling does not in the main appear to be a distinct clinical
subtype but rather a transient complication in 20% in the long-term course of bipolar disorder. Major depressions
superimposed on cyclothymic oscillations represent a more severe variant of bipolar II, often mistaken for borderline or other
personality disorders in the dramatic cluster. Moreover, atypical depressive features with reversed vegetative signs, anxiety
states, as well as alcohol and substance abuse comorbidity, is common in these and other bipolar patients. The proper
recognition of the entire clinical spectrum of bipolarity behind such masks has important implications for psychiatric
*Corresponding author. VA Psychiatry Service (116A), 3550 La Jolla Village Drive, San Diego, CA 92161, USA. Tel.: 1 1-619-552-8585
ext. 2226; fax: 1 1-619-534-8598.
E-mail address: hakiskal@ucsd.edu (H.S. Akiskal).
0165-0327 / 00 / $ see front matter 2000 Elsevier Science B.V. All rights reserved.
PII: S0165-0327( 00 )00203-2
S6
H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30
research and practice. Conditions which require further investigation include: (1) major depressive episodes where
hyperthymic traits lifelong hypomanic features without discrete hypomanic episodes dominate the intermorbid or
premorbid phases; and (2) depressive mixed states consisting of few hypomanic symptoms (i.e., racing thoughts, sexual
arousal) during full-blown major depressive episodes included in Kraepelins schema of mixed states, but excluded by
DSM-IV. These do not exhaust all potential diagnostic entities for possible inclusion in the clinical spectrum of bipolar
disorders: the present review did not consider cyclic, seasonal, irritable-dysphoric or otherwise impulse-ridden, intermittently
explosive or agitated psychiatric conditions for which the bipolar connection is less established. The concept of bipolar
spectrum as used herein denotes overlapping clinical expressions, without necessarily implying underlying genetic
homogeneity. In the course of the illness of the same patient, one often observes the varied manifestations described above
whether they be formal diagnostic categories or those which have remained outside the official nosology. Some form of
life charting of illness with colored graphic representation of episodes, stressors, and treatments received can be used to
document the uniquely varied course characteristic of each patient, thereby greatly enhancing clinical evaluation. 2000
Elsevier Science B.V. All rights reserved.
Keywords: Bipolar spectrum; Epidemiology; Bipolar I; Bipolar II; Bipolar III; Antidepressant-induced hypomania; Rapid-cyclings; Mixed
state; Life charting
1. Introduction
What today is officially termed bipolar disorder
has been recognized throughout much of this century
as manic-depressive psychosis. Nonetheless,
Kraepelin (1921) had included in the latter rubric
many recurrent depressive conditions that he considered to belong to manic-depression either on the
basis of lesser degrees of excitement (hypomania),
temperamental dispositions of a cyclothymic, irritable or manic types, or family history for manicdepressive illness. In current classificatory schemas
formally adopted by the American Psychiatric Association (DSM-IV, 1994) and the World Health
Organization (WHO, 1992), Kraepelins position has
been compromised in favor of unipolar and / or major
depressive disorders. What is retained in the bipolar
category conforms to a narrower definition of the
illness in which manic excitement, often of psychotic
proportion, alternates with depression; while hypomania is recognized, its diagnostic threshold is set
too high with many exclusionary clauses. As a result,
publications deriving from instruments or research
based on such conservative criteria, have estimated
bipolarity to account for about 1% of the population,
and only for 1015% of all mood disorders (Regier
et al., 1988; Weissman et al., 1996).
This paper challenges these rates for bipolar
disorder in light of a broader concept of bipolarity
which has evolved during the past two decades
(Akiskal, 1983, 1996, 1999), and which embraces a

spectrum involving schizomanic and manic (Gershon
et al., 1982; Marneros, 1999), as well as predominantly depressive expressions with hypomania and /
or cyclic recurrent course, including rapid-cycling
(Dunner et al., 1976, 1977; Angst, 1998). We will
document that patients with major depressions and
spontaneous hypomania as well as those with
hypomanic or manic episodes occurring during antidepressant treatment belong to the bipolar spectrum. An important thrust of recent research within
the bipolar spectrum is the greater recognition of
manic and depressive admixtures variously termed
mixed mania, depressive mania, or dysphoric
mania. Again we review the need and evidence for
less restrictive definitions for these bipolar mixed
states (McElroy et al., 1992; Perugi et al., 1997).
Finally, we consider the usefulness of charting the
course of affective illness (Leverich and Post, 1998)
as a way of better documenting and following the
progress of the entire spectrum of affective
manifestations for a given bipolar patient.
The recognition of the entire clinical spectrum of
bipolar disorders is of major public health concern
because, despite the increasing availability of new
treatments, under-diagnosis or long delay in diagnosis, and gross under-treatment continue to plague
our field (Lish et al., 1994; Hirschfeld et al., 1997).
Lesser manifestations often of a subthreshold,
depressive or labile nature and intermixed with
conduct disturbances precede the overt manifestations of the illness in the offspring and biological kin of adult bipolars (Akiskal et al., 1985).
Clinicians must be prepared to embrace a broader
view of bipolarity if such antecedents are to be
appreciated as possible indicators of the disease.
Although a plea, on methodological grounds, has
been recently made to maintain the integrity of the
bipolar disorder concept and to prevent its premature widening and dilution (Baldessarini, 2000), a
great deal of sound clinical research reviewed in this
paper justifies considerable widening beyond the
conservative positions of DSM-IV and ICD-10.
Where the evidence is inconclusive or tenuous, we
have refrained from endorsement of bipolar status for
border conditions, which would require more
systematic data.
2. Concepts and terminology

Although the connection of melancholia to mania
had been observed by Greek physicians about 2000
years ago, it wasnt fully documented in clinical
practice until the 19th century when French alienists
(Baillarger, 1854; Falret, 1854) and the German
psychiatrist Kraepelin (1921) devoted detailed descriptions to alternating forms of depression and
excitement in their psychotic, as well as milder,
ambulatory forms. The unipolarbipolar distinction
(as proposed, among others, by Angst, 1966 / 1973
and Winokur et al., 1969), gained momentum during
the last third of the 20th century, with the net result
of uncoupling depressive disorders from more strictly defined bipolar disorders. This distinction, which
has proven to be of great heuristic value for clinical
research, left undefined many affective conditions
lying in the interface of unipolar and bipolar disorders (Winokur, 1980). We learn about these patients when we examine the pedigrees of bipolar
probands and discover many affected individuals
with predominantly depressive manifestations (Gershon et al., 1982; Tsuang et al., 1985; Akiskal et al.,
1985b). Based on such data and clinical observations, Akiskal and Mallya (1987) estimated that
45% of the general population belongs to a broad
bipolar spectrum with predominantly depressive
phenomenology coupled with less-than-manic excitements. This enlarged concept of bipolar disorder,
S7
which incorporates cyclic depressions, has been

embraced by the definitive contemporary text on
manic-depressive illness (Goodwin and Jamison,
1990).
Originally, Dunner et al. (1976) identified these
less-than-manic patients as bipolar II on the basis of
hospitalization for depression, and excited periods
that did not require hospitalization. Fieve and Dunner (1975) had reserved bipolar I for those bipolar
patients whose excitements were of such severity
that hospitalization had been required. Although one
can argue that hospitalization is an artificial criterion
for defining the diagnostic threshold for mania, the
work of these authors nonetheless represented an
important advance for both research methodology
and clinical work in paving the way for the
recognition of the large universe of bipolar patients
whose excited periods remained ambulatory.
The soft bipolar spectrum (Akiskal and Mallya,
1987) is a more inclusive term for bipolar conditions
beyond classic mania, and which modifies the
foregoing definitions of bipolar II by incorporating
depressions with hypomanic episodes, cyclothymic
and hyperthymic traits, as well as those with familial
bipolarity; the spectrum also includes hypomanic
periods which occur during pharmacotherapy or
other somatic treatments. Alternative terms used in
referring to these less-than-manic bipolar conditions
with depressive presentation include Dm (Angst
et al., 1980), Unipolar-L (Kupfer et al., 1975),
and pseudo-unipolar depression (Mendels, 1976).
The last two designations do highlight the provocative possibility that many apparently unipolar patients could be related to bipolar disorder on the
basis of pharmacological response to lithium carbonate (Bowden, 1978).
Taylor and Abrams (1980), Akiskal et al. (1983),
and Egeland (1983) were among the first to urge for
the necessity to return to a broader concept of bipolar
disorder. Klerman (1981) spoke of a spectrum of
manic conditions that extended from classic psychotic mania through various degrees of hypomania,
subclassified into six types. A related proposal made
by Endicott (1989) extended the spectrum to include
cyclic depressions without clear-cut hypomania
but abrupt onset and offset. In a series of more
formal bipolar spectrum proposals (Akiskal, 1983,
1996; Akiskal and Akiskal, 1988), bipolarity is
categorized into type I (mania with or without
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depression), type II (depression with hypomania and /

or cyclothymia), and type III (hypomania associated
with antidepressants, as well as depressions with
hyperthymic temperament and / or bipolar family
history). Just a few years after the publication of
DSM-III and in response to a request by the
American Psychiatric Association as to whether the
new diagnostic manual provided adequate coverage
for all affective diagnoses in a consecutive case
series of personally examined affective states (Akiskal and Mallya, 1987), the foregoing bipolar spectrum
conditions were shown to be at least as prevalent as
their unipolar counterparts (Table 1).
The spectrum concept of bipolarity has been
greatly enriched by the epidemiological studies of
Angst (1998), who demonstrated the high prevalence
of brief hypomanic episodes below the threshold of 4
days required in such formal classifications as the
DSM-IV. This work, conducted by one of the
original group of researchers who was highly influential in promoting the unipolarbipolar dichotomy (Angst, 1966 / 1973), persuasively argues for
the need to enlarge bipolarity at the severe (psychotic manic) and the subthreshold (brief hypomania)
ends of the spectrum. What is remarkable here is that
the so-called subthreshold manifestations from a
symptomatological point of view have proven in
association with depression to have significant
adverse psychosocial consequences.
The important research of Bertelsen et al. (1977)
is perhaps the most convincing evidence for the
broad concept of bipolarity: Monozygotic twins
discordant for strictly defined mood disorders, were
broadly concordant for such conditions as moodlabile temperaments at the milder (untreated) end of
Table 1
Primary affective diagnoses in 102 patients a in a community
mental health centre b
Diagnosis
Bipolar I
Bipolar II
Bipolar III
Cyclothymia
Unipolar
Dysthymia
18
18
9
5
44
6
a
This sample is based on taking every 50th patient over a
10-year period and eliminating those with non-affective diagnoses.
b
Based on Akiskal and Mallya (1987).
the spectrum and mood-incongruent psychoses

beyond the boundaries of the classic affective psychoses at the severe end of the spectrum.
Two recent review papers represent contrasting
views on the boundaries of bipolar disorder. Cassano
et al. (1999) declare the bipolar spectrum to be a
clinical reality in search of diagnostic and assessment methodology. The other paper by Baldessarini
(2000) argues for a more cautious approach which
would restrict any broadening of the presently accepted official boundaries; it is curious, however,
that Baldessarinis tabulation of the historical evolution of the bipolar concept includes largely authors
or investigators whose work supports a broad concept of bipolar disorder. This is because the thrust of
historical development in bipolar disorder has been
for a broad spectrum. Indeed, a great deal of work
has been done in validating such a concept, including
clinically usable criteria. Where the Baldessarini and
Cassano approaches come together is their requirement of methodological purity which may be necessary for certain research operations versus practice
considerations which, we would contend, do not
require pristine methodological designs, nor unwieldy assessment instruments which are unrealistic
in a clinical setting.
To recapitulate, candidates proposed for inclusion
in a broadly conceived bipolar spectrum are
schizobipolar disorder, mania, mixed states, depressions with hypomania (irrespective of duration) or
pharmacologically mobilized hypomania, as well as
those in association with cyclothymic and hyperthymic temperaments, and finally recurrent (pseudounipolar) depressions with bipolar family history or
cyclic depressions responsive to lithium (and by
extension to other mood stabilizers). Because there is
relatively little controversy about manic states, much
of this paper enlarges upon the lesser-known entities
within the bipolar spectrum.
3. Epidemiological studies
Factors which influence rates of psychiatric disorders and particularly those for bipolar spectrum
disorders are listed in Table 2. Historically,
epidemiological research has neglected the less-thanmanic forms of bipolar disorder. An exception is a
study by Weissman and Myers (1978) which, using

Table 2
Methodologic factors influencing rates of bipolarity
?
?
?
?
?
?
?
?
Breadth of criteria
Instrument used
Lay versus clinical interviewers
Population studied (e.g., students, community subjects)
Sample size
Single versus repeated observations
Interview of patient versus relatives
Timing of interview
The Schedule for Affective Disorders and Schizophrenia (SADS), reported on bipolar I, II, and
cyclothymic personality in New Haven. However,
the difficulties of case ascertainment have generally
led to the subsequent exclusion of the symptomatologically milder expressions of bipolarity
(Weissman et al., 1996). This is exactly the opposite
of what has happened in the epidemiology of depression, which has focused on the entire severity of
depressive disorders (Angst and Merikangas, 1997;
Judd et al., 1997).
It is therefore not surprising that the rates for
bipolar disorder, based primarily on ascertaining
history of mania, have been under 1%. The same is
even more true for bipolar II disorder. Table 3
provides a breakdown of different studies conducted
in many countries since the availability of structured
diagnostic interviewing tapping criteria such as
DSM-III and beyond. Two national studies undertaken in the USA have had a major impact on the
rates of bipolar disorder which are cited in the
literature. These are the Epidemiological Catchment
Study (ECA, Regier et al., 1988) and the National
Comorbidity Survey (NCS, Kessler et al., 1994). The
rates are, respectively, 1.2% and 1.6%. Another
influential study (Weissman et al., 1996), compared
rates in different countries reporting a cross-national
range of 0.31.5%. All of these rates were observed
Table 3
Lifetime prevalence rates of bipolar disorder
Rate (%)
Regier et al. (1988) / USA

Kessler et al. (1994) / USA
Lewinsohn et al. (1995) / USAa
Weissman et al. (1996) / cross national

Szadoczky
et al. (1998) / Hungary a
Angst (1998) / Switzerland a
1.2
1.6
5.7
0.31.5
5.0
8.3
Emerging new data.
when conforming to narrow definitions of bipolar

disorder as reflected by instruments in which bipolar
II is inadequately defined.
Relatively new epidemiological data (also listed in
Table 3) have challenged the foregoing figures.
These data expand the concept of bipolar disorder to
include subthreshold expressions of hypomania, including those with less than 4 days. Thus, the new
rates include mania, hypomania, brief hypomania,
and cyclothymia. The most extensive of these studies
were conducted by Angst (1998) in the canton of
Zurich, and yielding rates for bipolar disorder up to
the age of 35 of 5.5% for DSM-IV mania and
hypomania, and a further 2.8% for brief hypomania.
The modal duration for these hypomanias, which
could be brief recurrent or sporadic, range from one
to three days. Lewinsohn et al. (1995), also using
broader definitions that went beyond the conventional duration thresholds for mania and hypomania,
found that 5.7% of adolescents in a community study
in Oregon met criteria for bipolar disorder. The
foregoing studies justify the inclusion of these
subthreshold conditions within the bipolar spectrum
on the basis of family history of mood disorders, a
history of suicide attempts, treatment seeking for
depression, or social impairments; comorbidity with
substance abuse and anxiety disorders was also high.
These high rates for bipolar disorders are not isolated

instances, because Szadoczky
et al. (1998) in Hungary have reported rates of 5% for bipolar spectrum
disorders.
In summary, the epidemiological literature from
community studies in the USA and several European
countries strongly favors the inclusion of soft bipolarity within the spectrum of bipolar disorders. Most
importantly, this emerging literature considerably
broadens the bipolar spectrum from the conventional
rate of 1% to at least 5%.
4. Characterizing cyclothymia, hypomania and
beyond
Author (year / country)
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4.1. Cyclothymia
Hypomania is critical for the definition of bipolar
spectrum conditions below the threshold of mania.
We will first document the phenomenology of hypomania in the course of cyclothymia, because most
studies on hypomania derive from cohorts with either
S10
cyclothymia or recurrent hypomania. The increased

rates for bipolar spectrum conditions in community
studies are in line with classic concepts of manicdepressive illness deriving from the work of such
authorities as Kraepelin (1921) and Kretschmer
(1936), who wrote about affective states which range
from the severest to the mildest, and which pass
without sharp boundary into the domain of personal
predisposition or temperament. Both described
cyclothymic individuals in whom low-grade affective
manifestations of a subdepressive and hypomanic
nature oscillated over long periods of the life span.
While in the classic, and especially German literature
(Schneider, 1959), cyclothymia refers to the entire
spectrum of manic-depressive manifestations, in its
current usage (Brieger and Marneros, 1997)
cyclothymic disorder is restricted to a subthreshold,
bipolar condition at the temperamental level.
In some cyclothymes (Akiskal et al., 1979a),
depressive or irritable moodiness predominates, in
others, trait hypomanic features (known as hyperthymic temperament) are more characteristic. These
could occur throughout life without progression to
major affective episodes, or represent predisposing
or prodromal phases to more severe episodic illness;
upon recovery from these episodes, patients tend to
return to their baseline temperament. Although largely neglected by the contemporary psychiatric establishment and clinical psychology, several large-scale
studies have examined cyclothymic disorder and its
variants. These studies differ from the strictly epidemiological studies just reviewed in that they focus
on clinical or student populations.
The first of these studies on subthreshold bipolarity was conducted at the University of Tennessee,
Memphis, USA, where Akiskal et al. (1977) reported
that slightly under 10% of a mental health clinics

patients conformed to subsyndromal mood changes
over extended periods of time. These were young
adults who presented clinically because of social
disruptions in their lives, such as romantic failure,
financial extravagance, repeated change of line of
work or college studies, frequent geographical
moves, and polysubstance abuse. The underlying
affective diathesis was validated on the basis of
phenomenological criteria that involved biphasic
subsyndromal changes in energy, activity, mood, and
cognition, each phase typically lasting from 2 days to
a week; some oscillated more in a depressive direction, others more in a hypomanic direction, but in
both directions at least at some point in their lives.
With Italian collaboration involving 1010, 1425
year old students (Placidi et al., 1998), high internal
consistency and diagnostic specificity has been found
for six of the eight criteria for cyclothymic temperament developed at the University of Tennessee
(Akiskal et al., 1979a). These revised criteria (listed
in Table 4) are thus more valid than their DSM-IV
and ICD-10 counterparts from both clinical and
psychometric standpoints. The subthreshold oscillation of hypomanic and subdepressive periods occurring in 6.3% of the population at large (Placidi et al.,
1998), represents a high-risk group predisposed to
major affective episodes (Akiskal et al., 1977,
1985b).
There has been much confusion in psychiatry
about the nature of predisposing traits to affective
disorder. Kraepelin (1921) spoke of personal predisposition, and Kretschmer (1936) referred to them
as affective temperaments. When affective oscillations are extreme and are associated with very
significant disruption and interpersonal conflict,
Table 4
Validated criteria for the cyclothymic a
Biphasic mood swings abrupt shifts from one phase to the other, each phase lasting for a few days at a time with infrequent euthymia. At
least four of the following which constitute the habitual long-term baseline of the subject:
? Lethargy alternating with eutonia
? Shaky self-esteem alternating between low self-confidence and overconfidence
? Decreased verbal output alternating with talkativeness
? Mental confusion alternating with sharpened and creative thinking
? Unexplained tearfulness alternating with excessive punning and jocularity
? Introverted self-absorption alternating with uninhibited people-seeking
a
Summarized from Akiskal et al. (1998).
many cyclothymic individuals would also meet

criteria for so-called borderline and other erratic
personality disorders. Indeed, this was the case in the
past records of the patients studied at Tennessee
(Akiskal et al., 1977, 1979a). The bipolar nature of
the disorder was confirmed by the propensity of the
more depressive cyclothymes to switch to hypomania
and / or mania on antidepressants, as well as family
history for bipolar disorders. Studies which have
started with borderline personality cohorts have also
found high rates of cyclothymic (Levitt et al., 1990)
and / or soft bipolar spectrum diagnoses (Deltito et
al., in press). In a German study (Sab et al., 1993)
which carefully rated subaffective personality disorders, borderline and irritable-cyclothymic conditions overlapped considerably. An authority on borderline conditions of the caliber of Stone (1988), has
declared irritable temperament to be the core underlying pathology in this personality type. It should not
come as a surprise that borderline personality has
been found to be a predictor of pharmacological
hypomania (Akiskal et al., 1985a; Levy et al., 1998).
The adjective borderline in many such instances
seems to refer to borderline manic-depressive psychosis (Akiskal et al., 1985a).
Commonly used personality tests tend to misattribute subaffective mood changes to borderline personality (OConnell et al., 1991).
Another large study examining cyclothymia was
conducted in college students in Albany, New York
(Depue et al., 1981; Klein et al., 1986).
Operationalizing from the criteria developed in the
University of Tennessee study and modifying
them on the basis of the classical psychiatric literature and psychometric considerations these authors reported that 46% conformed to cyclothymic
disorder. Apart from the fact that cyclothymia was
significantly higher among the offspring of bipolars
versus control subjects, the tendency of many of
these cyclothymic students to develop depressive
and / or suicidal states as well as substance abuse
during prospective observation pointed to a
strong bipolar diathesis.
4.2. Hypomania
Accurate assessment of hypomania is critical for
the proper identification of the less-than-manic spec-
S11
trum of bipolar disorders. Unfortunately, the criteria

for hypomanic episodes as described in DSM-IV
(1994) are insufficiently distinct from those for
mania. We agree with the stipulations that the
characteristic features of hypomania must be observed by others and that psychotic symptoms should
be absent. Thus, major life disruptions are uncharacteristic indeed hypomania is sometimes adaptive
(Akiskal et al., 1977; Jamison et al., 1980). Tables 5
and 6 list the rich phenomenology of hypomania
observed, respectively, in the Memphis (Akiskal et
al., 1979a,b) and Zurich (Wicki and Angst, 1991)
studies both of which go beyond the narrow range
of clinical presentations listed in DSM-IV and ICD10.
The studies thus far reviewed on cyclothymia and
hypomania were conducted largely before the availability of DSM-IV, and they are unanimous in validating a duration for hypomania shorter than 4 days.
The Akiskal et al. (1979b) study specified a 2-day
duration, and the Zurich study (Wicki and Angst,
1991) found a modal duration of 13 days. It is also
apparent from these studies that recurrence of hypomania is a characteristic of disorders in the softer
spectrum. Therefore, the 4-day threshold of DSM-IV
is unjustified and unnecessarily narrows down the
range of bipolar spectrum disorders diagnosable in
clinical and epidemiological studies. Actually, a very
large Italian clinical study on bipolar II patients
(Cassano et al., 1992), which used a definition of
hypomanic duration of 2 days whether it was
episodic or part of cyclothymia found that these
patients had rates of bipolar family history statisticalTable 5
Signs and symptoms of a hypomanic episode based on a clinical
sample a
Three or more of the following, which must represent departure
from patients habitual baseline for $ 2 days
? Cheerfulness and jocularity
? Gregariousness and people-seeking
? Heightened sexual drive and behaviour
? Talkativeness
? Overconfidence and overoptimism
? Disinhibition and carefree attitudes
? Hyposomnia
? Eutonia and vitality
? Over involvement in new projects
a
Expanded from Akiskal et al. (1977, 1979a,b).
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Table 6
The most common manifestations of hypomania in a community
study a
Less sleep
More energy, strength
More self-confidence
Increased activities (including working more)
Enjoying work more than usual
More social activities (i.e., telephone calls, visiting other people)
Spending too much money
More plans and ideas
Less shy, less inhibited
More talkative than usual
Increased sex drive
Increased consumption: coffee, cigarettes, alcohol
Overly optimistic / euphoric
Increased laughter (making jokes, puns)
Thinking fast / sudden ideas
a
Summarized from Angst (1998).
ly indistinguishable from that of bipolar I disorder,

both of which were significantly higher than that of
major depressive disorders.
4.3. Hyperthymia
There have also been studies that have focused on
subthreshold lifelong hypomanic symptoms. Eckblad
and Chapman (1986) studied college students at the
University of Wisconsin: Six percent met lifetime
criteria for hypomanic tendencies that, interestingly,
in some cases were associated with mini-depressive
dips. In the Pisa-San Diego collaborative study
(Akiskal et al., 1998; Placidi et al., 1998), also
conducted among students, 8% could be categorized
as hyperthymic on the basis of the entire complement
of seven persistent hypomanic traits (Akiskal, 1992).
These psychometrically established traits are as
follows: (1) Warm, people-seeking or extroverted;
(2) cheerful, overoptimistic or exuberant; (3) uninhibited, stimulus-seeking or promiscuous; (4) overinvolved and meddlesome; (5) vigorous, full of
plans, improvident or carried away by restless impulses; (6) overconfident, self-assured, boastful,
bombastic or grandiose; (7) articulate and eloquent.
These criteria are also validated on the basis of
family history in that clinically depressed patients
who met five or more of these criteria, had rates of
familial bipolarity significantly higher than strictly
unipolar patients without these temperamental attributes, and indistinguishable familially from bipolar
II patients (Cassano et al., 1992). The possible

inclusion of these hyperthymic depressives within
the bipolar spectrum (Akiskal and Akiskal, 1988;
Akiskal and Pinto, 1999) depending on the
threshold of the diagnosis of hyperthymic temperament will shrink unipolarity by 1020% (Cassano
et al., 1992). Current data are uncertain about the
boundary of hyperthymic temperament and normality
(Akiskal et al., 1998); this temperament as currently
measured may be considered abnormal only in the
presence of clinical depression. Further research in
this area will be important for both clinical and
genetic investigations.
4.4. The question of axis II

There is an extensive literature based on clinical
and community samples which validates the definition of hypomania at a threshold lower than that set
in DSM-IV. In particular, hypomania emerges as a
condition with a duration threshold of 2 rather than 4
days; in recurrent brief hypomania, a duration of 1
day would suffice. Furthermore, in a special subgroup, hypomanic manifestations persist over a
lifetime in a trait-like fashion: these hyperthymic
individuals have been excluded from official classifications, but their importance lies in the fact that the
depressive episodes which occur in such individuals
are from a familial standpoint no different from those
with bipolar II disorder.
Finally, the concept of cyclothymic disorder as
defined in ICD-10 and DSM-IV would benefit from
better operationalization: what is crucial here is the
biphasic oscillation of subthreshold hypomanic and
depressive manifestations over long periods of lifetime. Many cyclothymic individuals develop clinical
depression and therefore should be considered as a
more complex form of bipolar II that might be
classified under cyclothymic depression (Akiskal,
1981, 1994; Akiskal and Pinto, 1999). Patients with
bipolar II disorder whose hypomanias are part of a
cyclothymic temperamental background, present
with greater interpersonal disturbances and are at risk
for being mislabeled borderline, histrionic and / or
psychopathic. From a therapeutic standpoint, much
is to be gained from considering such flamboyant
individuals with erratic mood swings as suffering
from a bipolar spectrum disorder. We submit that
patients presenting with fluctuating affective symp-
toms, the diagnosis of a bipolar spectrum diagnoses

should take precedence over that of a personality
disorder within the dramatic cluster.
5. Bipolar II
5.1. Clinical diagnosis

This subtype refers to a common clinical situation
where the patient presents with a major depressive
episode, and upon further inquiry, history for hypomanic episodes is elicited. Accurate diagnostic
subtyping then depends on the vagaries of the
patients memory and how rigorously the clinician
pursues lead questions about hypomania and,
most importantly whether relatives are interviewed.
Otherwise, unless recorded in the patients past
psychiatric chart, the examining clinician may have
little clue from the patients current depressive
mental state about the bipolar elements in the
patients history. Accordingly, rates of bipolar II
disorder were, until recently, underestimated.
The under-diagnosis of bipolar II disorder due to
under-reporting of hypoania is of critical importance
for both clinical practice and genetic investigations.
John Kelsoe, M.D., who heads the Bipolar Genetics
Program at the University of California at San Diego
(personal communication, March 31, 2000) summarized the diagnostic problem as follows: The major
problem . . . in diagnosis is state dependent memory
in patients. When they are high, all they remember
are past manias, when they are depressed, they only
recollect being depressed. I have seen many patients
for whom we had thoroughly eliminated any history
of hypomania from repeated interviews during the
depressed state, only to find that when they became
hypomanic on an antidepressant, they suddenly
remembered many past hypomanias. There is much
support for this in both animal and human studies of
memory.
The foregoing considerations are of the utmost
importance in the diagnostic workup of bipolar II
patients. There have been two related methodological
developments published in the recent literature with
respect to this question. The first is by Rice et al.
(1986), who in the context of the NIMH collaborative study of depression, reported that although the
S13
reliability of the bipolar II diagnosis was low, all

such diagnoses occurred in pedigrees with bipolar
disorder, suggesting that once hypomania was identified in association with major depressive disorder,
it did carry great diagnostic specificity. What this
means in practice is that the diagnosis of bipolar II
cannot be made in cross-section, but should be based
on repeated evaluations. The other and related methodological point was made by Dunner and Tay
(1993), who found that clinicians specifically trained
to recognize bipolar II, far outperformed structured
instruments such as the SADS or the SCID in the
diagnosis of bipolar II disorder. Both methodologic
points cohere with recommendations made by Akiskal et al. (1977) that the diagnosis of hypomania
among cyclothymic subjects be based on repeated
expert interview. Although these points go against
the usual tenets in the literature on structured interviewing, they are consistent in suggesting that the
proper identification of bipolar II requires a more
sophisticated approach in interviewing and diagnosis.
Another way to say this is that, because many
bipolar II patients have an underlying temperamental
dysregulation, their clinical presentations are varied
and inconsistent and often prove confusing in crosssection. That is, they could present with cross-sectional features of atypical depression, and lifelong
history of anxiety states, bulimia, substance abuse,
and personality disorder (Perugi et al., 1998; Benazzi, 1999). Bipolar II is a complex diagnosis because
it often encompasses many of these comorbid
conditions; a prospective study has also demonstrated that atypical depressions more often than not
progress to bipolar spectrum disorders (Ebert et al.,
1993). Faced with patients with atypical depressive
features as defined in DSM-IV, the clinicians task is
to identify a pattern of cyclic depressions with
distinct hypomanic periods as the core unifying or
underlying diagnosis behind their varied comorbid
manifestations.
The question of bipolar II-anxious comorbidity is
beyond the scope of the present review. Suffice it to
say that, though counterintuitive, it appears to have a
stronger genetic basis than bipolar II without panic
attacks (MacKinnon et al., 1998). The affective
dysregulation of bipolar disorder obviously extends
beyond elation and depression to include, among
others, such negative affective arousal states as
panic, irritability, and mood lability.
S14
5.2. The specificity of mood lability

How should then a clinician optimally approach
the diagnosis of bipolar II? Analyses from the NIMH
Collaborative Depression Study on unipolar patients
who switched to bipolar II may help in this regard.
Of 559 patients with major depressive disorder at
entry, 48 converted to bipolar II during a prospective
observation period of 11 years (Akiskal et al., 1995).
What characterized these bipolar II converters at
entry was early age at onset of first depression,
recurrent depression, high rates of divorce or separation, high rates of scholastic and / or job maladjustment, isolated antisocial acts, drug abuse in
brief, a more tempestuous affective and life history.
In addition, the index depressive episode was further
characterized by such features as phobic anxiety,
interpersonal sensitivity, obsessivecompulsive
symptoms, somatization (often with subpanic symptoms), worse in evening, self-pity, demandingness,
subjective or overt anger, jealousy, suspiciousness,
and ideas of reference again testifying to a broad
melange
of atypical depressive symptoms with
borderline features. Temperamental attributes obtained at index interview proved decisive
(sensitivity 5 91%) in identifying those who
switched from depression to hypomania: these attributes consisted of trait mood lability, energy
activity, and daydreaming all characteristic of
Kretschmers (1936) description of the cyclothymic
temperament; mood lability was the most specific
predictor (specificity 5 86%) of which depressions
will prospectively change to bipolar. This study
testifies to the fact that bipolar II disorder is a
complex affective disorder with biographical instability deriving more often than not from an
intense temperamental dysregulation. Mood lability
with rapid shifts, often in a depressive polarity
was the hallmark of unipolar patients who
switched to bipolar II. The foregoing characteristics
revealed in a prospective study on a large clinical
cohort in five university centers provide a pattern
recognition which clinicians can use in their diagnostic evaluation for ascertaining bipolar II disorder and
its variants. Unfortunately, our formal diagnostic
systems (e.g., ICD-10 and DSM-IV) are symptomoriented and do not consider extreme temperamental
dispositions in clinical evaluation; also regrettably
such patients often get labeled borderline. The
TEMPS or Temperament Evaluation of Memphis,

Pisa, Paris, and San Diego (auto-evaluation version,
Akiskal et al., in press) should ultimately help in the
proper identification of the soft bipolar spectrum.
5.3. Clinical prevalence of bipolar II in major

depression
The diagnosis of bipolar II is crucial, not only
because of its therapeutic implications, but also for
prognostic reasons. Since Dunner et al. (1976)
pioneering report, the literature has supported the
risk for high suicidality in this group of patients
(Rihmer and Pestality, 1999). Accordingly, it is
gratifying that a great deal of research has been
conducted on the clinical prevalence of bipolar II
among patients presenting with major depressive
disorder to various medical centres and clinics
worldwide. What emerges is that from 3055% of all
major depressions conform to the bipolar II or its
variants: It is noteworthy that the data are not limited
to academic centers that specialize in mood disorders
(Akiskal and Mallya, 1987; Cassano et al., 1992), but
include at least two large outpatient psychiatric
private practice settings (Koukopoulos et al., 1980;
Benazzi, 1997b). Nor are these high rates limited to
psychiatric settings; at least one such report has
come from a family practice clinic (Manning et al.,
1997). Moreover, according to Simpson et al.
(1993), bipolar II may represent the most common
phenotype of bipolar disorder.
The French EPIDEP study (Hantouche et al.,
1998) based on a clinical sample from a variety of
hospital and clinical settings private and public,
inpatient and outpatient, academic and general psychiatric sector have provided the most compelling
data on the high prevalence of bipolar II among
major depressive patients. The overarching purpose
of this study was to assist practicing psychiatrists to
recognize bipolarity in all of its varieties. Preparatory
to the ambitious aim of obtaining national data on
the full spectrum of bipolar disorders, 40 round
tables were conducted in six regions of France
involving 650 psychiatrists. This culminated in a
Paris symposium attended by senior French professors of psychiatry, directors of ambulatory clinics
and hospitals, as well as other opinion leaders. These
training activities over a period of 30 months addressed the gaps between the classic (Baillarger,
1854; Falret, 1854; Kraepelin, 1921) and the current

literature on the one hand, and current diagnostic
practice based on ICD-10 and DSM-IV systems on
the other. New data in support of the classic literature was extensively discussed, especially regarding
the high prevalence of depressive conditions with
mild excitement (Akiskal et al., 1979a,b; Akiskal,
1983; Egeland, 1983; Akiskal and Akiskal, 1988;
Cassano et al., 1992; Simpson et al., 1993), as well
as the high prevalence of temperamental dysregulation in many patients with cyclic or bipolar II
depressives (Akiskal et al., 1979a, 1995; Cassano et
al., 1992). The foregoing activities culminated in the
establishment of a co-ordinating body consisting of
Drs Hantouche, Akiskal, plus Allillaire, Azorin,
Bourgeois and Sechter from different regions of
France, and the construction of a semi-structured
interview schedule modified from DSM-IV and
incorporating various rating scales and the French
translation of temperamental attributes from an early
version of the TEMPS-A (Hantouche and Akiskal,
1997). The major finding of this study, reported on
the first 250 patients evaluated nationally (Hantouche
et al., 1998) indicated that at index interview 22% of
major depressive patients could be diagnosed as
bipolar II based on past history of hypomania; a
month later, upon re-interview, 40% of patients were
diagnosed as bipolar II on the basis of more in-depth
evaluation and collateral information from significant
others, as well as observed hypomania by the
clinician.
The question is often raised whether patients with
bipolar II disorder represent an autonomous type of
bipolar illness or a transitory condition between
unipolar and full-blown bipolar disorder with mania.
It is beyond the scope of this paper to address this
complex issue, but suffice it to say that in patients
with at least a 5-year history of affective illness,
those with the bipolar II diagnosis represent a stable
condition that rarely progresses to bipolar I disorder
(Coryell et al., 1995).
5.4. The question of pharmacological hypomania

Another burning question, vital for private practice, pertains to hypomania that becomes first manifest upon pharmacological challenge with antidepressants. Based on Lewis and Winokur (1982), Angst
(1985), and Kupfer et al. (1988), both DSM-IV and
S15
ICD-10 have denied distinct bipolar status to these

patients. This is a regrettable decision, a more
extensive literature existed before the publication of
DSM-IV, strongly in favour of including such patients within the rubric of bipolar disorders (Bunney
et al., 1972; Akiskal et al., 1979b, 1983; Strober and
Carlson, 1982; Wehr and Goodwin, 1987; Sultzer
and Cummings, 1989) and new reports (Altshuler
et al., 1995; Menchon et al., 1993; Benazzi, 1997a;
Post et al., 1997) have been published since then.
Mood stabilizers do not seem to fully prevent
antidepressant-associated switches (Bottlender et al.,
1998), though an adequate level of a mood stabilizer
might be protective (Jann et al., 1982). Antidepressant-mobilized hypomanic episodes tend to be somewhat milder (Stoll et al., 1994), less likely to occur
with SSRIs compared with tricyclics (Peet, 1994;
Bottlender et al., 1998), and more euphoric with
monoaminoxidase inhibitors than tricyclics which are
likely to induce more dysphoric hypomania (Himmelhoch et al., 1991). However, during prospective
observation, nearly all adult patients with antidepressant-associated hypomanic episodes progress months
or years later to bipolar states with spontaneous
hypomania or mania (Akiskal et al., 1983); this also
is true for adolescent depressives (Strober and Carlson, 1982). Table 7 summarizes the most sensitive
and specific parameters in the prospective prediction
of bipolar outcome and pharmacologically occasioned hypomania tops the list.
What has been reviewed thus far, indicates that
bipolar II is a prevalent condition accounting for
one-third to one-half of all major depressive states
encountered in clinical practice. Those with pharmacologically mobilized hypomania seem to represent a
variant of the bipolar II pattern that can be provisionally termed bipolar III. The data listed in Table 7
further suggest that depressions with bipolar family
should be closely observed for eventual bipolar
transformation. Observed hypomania on antidepressants may represent the first gross indication for such
transformation. Systematic interviewing may often
reveal spontaneous hypomanic excursions buried in
the past history which had been considered
normal mood fluctuation. It is noteworthy, too, that
antidepressant-associated hypomania is not limited to
major depressions. It could occur in dysthymic
patients (Rosenthal et al., 1981; Rihmer, 1990), as
well as social phobic, obsessivecompulsive, and
S16
Table 7
Diagnostic performance of variables significantly associated with
bipolar outcome a
Variable
Sensitivity
(%)
Specificity
(%)
Pharmacological hypomania
Bipolar family history
Loaded pedigrees
Hypersomnic-retarded depression
Psychotic depression
Postpartum onset
Onset of depression before age 26
32
56
32
59
42
58
71
100
98
95
88
85
84
68
Summarized from Akiskal et al. (1983).
other anxiety states (reviewed in Himmelhoch, 1998

and Perugi et al., 1999). In brief, the depressive
phase of bipolar II patients can, in a significant
minority of patients, be replaced by subthreshold
depressive, socially anxious or obsessive inhibitions.
These clinical observations, which require greater
research validation, are quite important in clinical
case management.
5.5. Soft bipolarity beyond bipolar II

The foregoing discussion has considered what
on the basis of rigorous data can be categorized
within a broad spectrum of bipolarity short of fullblown mania and extending into the realm of temperament. It is beyond the scope of this paper to
consider the differential diagnosis of adult attentiondeficit hyperactivity disorder (ADHD) and bipolar II.
Suffice it to say that history for childhood hyperactivity is more common in adult bipolars than unipolars (Winokur et al., 1993), and that increased sexual
drive, grandiosity and psychosis are uncharacteristic
of ADHD (Weller et al., 1995). Nor have we
considered in requisite depth mood, alcohol and
stimulant abuse comorbidity (Regier et al., 1988;
Winokur et al., 1998; Sonne and Brady, 1999),
which should be carefully evaluated for bipolar
spectrum diagnoses. Regrettably, DSM-IV conventions tend to favor diagnosis of alcohol and substance abuse at the expense of bipolar disorders.
When in doubt, faced with a patient who exhibits
joint problems of substance abuse and unrelenting
mood swings, it would often prove clinically advantageous to err in favor of bipolar spectrum diagnoses
for which specific treatment options exist.
In this review, we have also omitted discussion of
other conditions, whose link to bipolarity is tenuous

(Akiskal and Pinto, 1999): these include atypical and
seasonal depressions without discernible hypomanic
states, which have periodicity and abrupt onset and
offset; other patients may present with episodic
obsessivecompulsive symptoms, periodic states of
irritability, or acute suicidal crises in the absence of
clear-cut affective symptoms; there are also patients
with cyclic episodic neurasthenic or sleep complaints
or those with severe brief recurrent depressions.
Lastly, McElroy et al. (1996) have drawn attention
to the possible bipolar nature of some impulse-ridden
behaviors such as those in the realm of aggression
control, gambling and paraphilias. All of these
conditions require further study before a definite link
to bipolarity can be claimed.
6. Rapid cycling
Patients with rapid-cycling disorder as defined in
DSM-IV and ICD-10 present a minimum of four
episodes per year, i.e., mania / hypomania and major
depression (Maj et al., 1994). They are most likely to
arise from a bipolar II base (Coryell et al., 1992)
and thus present with at least four alternating depressive or hypomanic episodes per year. Alternating is
the correct verb, because such patients do not
typically have respite from affective episodes during
the rapid-cycling phase of their illness.
Rapid-cycling patients lie along a spectrum based
on the duration of episodes which, by definition,
must meet the symptom severity thresholds for
mania / hypomania and depression. Rapid ( $ 4 /
year), ultra-rapid ( $ 4 / month), and ultradian
( $ within a day) cycling patterns can be recognized
clinically; they are distinguished from cyclothymic
disorder which pursues a subthreshold course as far
as symptoms.
In rapid cycling, bipolar illness takes on a roller
coaster course for both patient, family, and the
physician. Rapid cycling appears to be on the rise
(Wolpert et al., 1990). Fortunately, this condition
which is reported to occur in 1356% of bipolar
patients (reviewed in Kilzieh and Akiskal, 1999),
appears to be a transient phase in the course of
bipolar disorder, rather than a distinct subtype
(Coryell et al., 1992); in 24 years, most rapid
cycling observed during naturalistic follow-up will
return to a less cycling pattern. The higher rates of

rapid-cycling are reported from research institutions
which specialize in refractory bipolar disorders; the
prevalence is less than 20% in most studies. Risk
factors discussed in the literature but not unanimously agreed upon include female sex,
cyclothymic temperament, borderline hypothyroidism, and possibly excessive use of antidepressants
(Koukopoulos et al., 1980; Wehr et al., 1988; Bauer
et al., 1994b). One recent meta-analysis (Tondo and
Baldessarini, 1998) found inconsistent association
with female sex. Such discrepancies are likely due to
methodologic differences in case definition and
inclusion.
Rapid cycling is typically a post hoc diagnosis.
This may be another explanation for some of the
discrepancies in the literature regarding risk factors.
Retrospective systematic analysis of large samples
may minimize biased observations. Thus, Perugi et
al. (2000) have shown that bipolar illness with
depression as the episode at onset, are significantly
more likely than manic and mixed state onsets to
develop rapid cycling, suicidal behavior, and psychotic symptoms; mixed onsets, too, had high rates
of suicide attempts, but differed from depressive
onsets in having significantly more chronicity yet
negligible rates of rapid cycling. The authors concluded that because those with depressive onset had
received significantly higher rates of antidepressant
treatment, the findings supported the hypothesis that
antidepressants may have played a role in the
induction of rapid cycling. Such a conclusion was
also reached by Akiskal et al. (1985b) in the juvenile
and young adult offspring of bipolar probands. These
considerations suggest that rapid cycling and mixed
states represent distinct patterns in the course of
bipolar disorder.
7. Bipolar mixed states

Mixed states, defined as simultaneous mixtures of
depressive and hypomanic symptoms, represented a
major line of evidence for Kraepelins concept
linking mania and depressive illness that was fully
enunciated in the 1899, sixth edition of his handbook
(Kraepelin, 1921, english translation). As a brief
transitional phase from depressive to manic episodes
or vice versa, they do not represent a specific
S17
psychopathological state. However, Kraepelin observed that full affective episodes with such admixtures did commonly occur during the course of
manic depressive illness. He described depressive
admixtures occurring during mania, as well as hypomanic intrusions into full depressive episodes. His
categorization included at least six types, of which
depressive or anxious mania, and agitated or excited
depression are the most prevalent in current clinical
practice. Although this broad definition of mixed
states is well accepted in European psychiatry
(Berner et al., 1992), it is not fully reflected in
ICD-10 (1992); the narrowest definition is that of
DSM-IV (1992) which requires fullfledged manic
and syndromal depressive manifestations.
Mixed states represent a new focus of clinical
research in mood disorders. There is no terminological uniformity in the literature, and there is a
regrettable tendency to use such terms as mixed
state, mixed mania, depression during mania,
and dysphoric mania interchangeably. Dilsaver et
al. (1999) have recently described different phenomenological subtypes within the larger manic
population. We will not attempt to review this
literature which is still inconclusive. In this report we
will briefly discuss the depressive mixed states
(major depressions with few hypomanic symptoms)
which, though of great clinical significance, remain
under-studied; and then focus on dysphoric mania
(Post et al., 1989), the most studied form of mixed
state in the literature and referring to manic conditions with such dysphoric features as irritability,
anxious depression, and hostileaggressiveparanoid
admixtures.
Hypomanic symptoms such as racing and grandiose thoughts, sexual arousal, and psychomotor
acceleration have been described in major depressive
episodes in contemporary psychiatry thereby
testifying to Kraepelins diagnostic acumen yet
the number of studies reporting on bipolar depressive mixed states are too few (Akiskal and Mallya,
1987; Koukopoulos and Koukopoulos, 1999; Perugi
et al., 1997). Unfortunately, such studies have not
commanded sufficient interest in official nosologic
systems, nor in the clinical literature. This is a
clinical tragedy because these are the very unipolar
depressive patients who are likely to do poorly
on antidepressants and require mood stabilizers,
antipsychotics, or electroconvulsive therapy.
S18
Koukopoulos and Koukopoulos (1999) have recently

written a superb clinical article on agitated depression as a mixed state. This is an instance where
clinical acumen has outpaced the conventional scientific literature.
We will be focusing the remainder of this section
to mixed states conceived as dysphoric mania. The
literature from Kraepelin until the last decade of the
20th century is sparse and has been masterfully
reviewed by McElroy et al. (1992). Alcohol abuse
and neuropsychiatric conditions are common in
mixed states (Himmelhoch et al., 1986). Mixed
states have been best characterized in female inpatients (DellOsso et al., 1991; Perugi et al., 1997;
Akiskal et al., 1998), often arising from a course of
illness with more depressive than manic episodes and
with a tendency to repeat over time (Perugi et al.,
2000). Family history is more often depressive than
manic (DellOsso et al., 1991), and suicidality is a
distinct risk (Dilsaver et al., 1993; Strakowski et al.,
1996; Goldberg et al., 1998). Confusion and psychotic features, including mood incongruence, are also
important clinical characteristics in cross section
(DellOsso et al., 1993; Perugi et al., 1997). An
average of at least 40% of all patients with bipolar
disorder give evidence at one point or another of
having a mixed state (Table 8); these rates vary,
depending on the criteria used (narrow or broad) and
whether the setting is a community hospital versus a
tertiary care or specialized bipolar unit. From a
diagnostic standpoint, the most important advance in
our understanding of mixed states has come from
studies during the past decade, and which indicate
that the DSM-IV threshold for syndromal depression
during mania is too restrictive in the diagnosis of
mixed mania. A large literature from both European
and US centres (Bauer et al., 1994a; McElroy et al.,
1995; Perugi et al., 1997; Swann et al., 1997;
Akiskal et al., 1998) suggest that few depressive
symptoms would suffice in validating the clinical
diagnosis of mixed mania.
The most convincing data comes from the French
EPIMAN study which was conducted in four centres
in France, and involving over 100 patients (Akiskal
et al., 1998). Like its companion EPIDEP, this study
involved extensive training for French clinicians and
academic opinion leaders about the emerging literature on dysphoric mania. Semistructured diagnostic
Table 8
Rates of mixed states in representative studies
Study
Winokur et al. (1969)
Kotin and Goodwin (1972)
Himmelhoch et al. (1976)
Akiskal and Puzantian (1979)
Nunn (1979)
Secunda et al. (1985)
Prien et al. (1988)
Post et al. (1989)
DellOsso et al. (1991)
McElroy et al. (1995)
Cassidy et al. (1998)
Akiskal et al. (1998)
Dilsaver et al. (1999)
Total
Patients (N)
61
20
84
60
112
18
103
48
108
71
273
104
105
16
65
31
25
36
44
67
46
45
40
14
37
40
1167
43
interviews were conducted derived from the DSM-IV

schema for mixed state, but with suspension of the
arbitrary DSM-IV threshold of full syndromal depression. Patients were also extensively tested psychometrically, including the French version of the
TEMPS (Hantouche and Akiskal, 1997). Because
patients were entered into the study on the basis of
meeting full criteria for index manic episodes, the
rates for strictly defined DSM-IV mixed states were
low, 6.7%. But using a cutoff of two or more
depressive symptoms, 37% could be characterized as
dysphoric manic. As expected, these patients scored
more than 10 on the modified Hamilton-D Scale.
Depressed mood and suicidal thoughts had the best
predictive diagnostic value for mixed mania. An
important finding of this study was that mixed manic
patients, compared with those with pure mania, had a
higher percentage of depressive temperamental traits.
Such data argue that mixed mania can be defined
categorically by two or more depressive symptoms,
psychometrically on the basis of HAM-D . 10, or
dimensionally on the basis of depressive temperamental traits similar to long-standing dysthymia.
The latter had also been observed in the Pisa-San
Diego collaborative study (Perugi et al., 1997)
supporting, hypothetically, the possibility that mixed
mania represents mania arising from a depressive
temperamental baseline i.e., a mixed state conceived as a reversal of temperament to its opposite
polarity (Akiskal, 1992).
There are no studies of mixed mania examining
prospectively the list of discriminatory depressive

symptoms developed by McElroy et al. (1992).
Based on the literature (Bauer et al., 1994a; Cassidy
et al., 1997, 1998; Akiskal et al., 1998), a constellation of largely emotionalcognitive symptoms appear as the most discriminatory (Table 9) and worthy
of further investigation. McElroy et al. (1992) proposed a cut-off of $ 3, Akiskal et al. (1998) $ 2,
and Swann et al. (1997) $ 1, depressive symptoms
in the midst of mania for the diagnosis of mixed
state. These are not mere nosologic nuances, because
even one depressive symptom during mania seems to
predict low response to lithium and good response to
divalproex (Swann et al., 1997).
8. Psychotic forms of mania

The literature amply testifies to the occurrence of
psychotic symptoms, including mood-incongruent
features, during manic episodes (Carlson and Goodwin, 1973; Taylor and Abrams, 1973; Pope and
Lipinski, 1978; Akiskal and Puzantian, 1979). These
have been incorporated into the DSM-IV and ICD-10
diagnostic schemas. Manic patients with such extreme psychotic manifestations appear as more severe versions of bipolar disorder. Discussion of
schizoaffective disorders, which are quite heterogeneous, is beyond the scope of the present review.
Suffice it to say that the schizomanic or
Table 9
Depressive symptoms to be evaluated in supporting a diagnosis of
dysphoric mania a
Discriminatory
? Depressed mood
? Irritability
? Mood lability
? Anhedonia
? Hopelessness / helplessness
? Suicidal ideation and / or attempt
? Guilt
? Fatigue
Nonspecific
? Agitation
? Insomnia
? Weight changes
a
Based on McElroy et al. (1992), Bauer et al. (1994a,b),

Cassidy et al. (1998), Akiskal et al. (1998).
S19
schizobipolar subtype may well represent an even

more severe course variant of bipolar disorder (Van
Eerdewegh et al., 1987; Marneros, 1999). What in
practice distinguishes this disorder from more classic
mania is the presence of mood-incongruent features
during mood-free intervals.
Differential diagnosis of manic and schizophrenic
patients does not present much difficulty in patients
who have had previous bouts of illness. The course
and distinctive clinical features of the two disorders
would, in most instances, lead to appropriate diagnostic assignment. The differential diagnosis is more
problematic in adolescent patients. Particularly
problematic are such symptoms as loose associations and flatness of affect (Akiskal, 1994). Regarding looseness, if this disturbance in the stream
of thought occurs in a manic psychosis, it would be
associated with pressure of speech, distractibility and
expansive mood, thereby clinching the diagnosis; by
contrast, in schizophrenia looseness occurs in the
context of derailment of thought, perseveration, and
restricted affect, again pointing to a diagnosis away
from a manic psychosis. As far as flatness, in an
affective psychosis, one would observe severe depression and slowed thinking; whereas, in a schizophrenic psychosis, flatness will be associated with
inappropriate affect and poverty of thought content.
In brief, in the differential diagnosis of affective and
schizophrenic psychoses, rather than depending on
pathognomonic signs, the clinician must be guided
by a pattern of signs and symptoms which are
characteristic of one rather than the other psychosis
(Andreasen and Akiskal, 1983).
There has been recent research in possible genetic
overlap between certain bipolar and schizophrenic
disorders (reviewed in Berrettini, 2000). Whether
these data argue for a continuum between the two
groups of disorders or a specific clinical subtype with
shared oliogenic diathesis is presently unresolved.
This question is beyond the scope of the present
review.
9. Life charting of patients course

Many clinical settings that specialize in the
evaluation and treatment of bipolar disorder utilize
some form of life charting a graphical method for
S20
detailing the course of manic-depressive illness that

was championed by Kraepelin (1921). A more
sophisticated version has been adopted and further
developed at the National Institute of Mental Health
(Leverich and Post, 1998) as a research tool to detail
the polarity and severity of episodes and their
longitudinal course. Significant biological (e.g.,
menarche, menopause, somatic disorders and their
treatment) and psychosocial events (e.g., marriage,
bereavement, geographical move, job loss) can be
easily highlighted. Most importantly, the treatments
and their impact on the course of the illness can be
documented. We submit that clinicians and patients! can easily learn this technique or a
simplified variant of it, adjusted to their specific
clinical needs, thereby optimizing record-keeping of
the course of illness and its progress under different
therapeutic conditions. The benefits of life charting
are summarized in Table 10, and the methodology
provided in greater detail in Appendix A.
10. Conclusions
Emerging data from several epidemiological
studies conducted both in the USA and abroad have
challenged the conservative figures of 1% commonly

cited in the literature for bipolar disorder. If one
were to include bipolar spectrum conditions, the
rates jump to 5% or even higher. Clinical studies
indicate that bipolar disorders may be nearly as
common as unipolar disorders. The new proposed
spectrum is in accordance with Kraepelins position
which proposed a manic depressive condition that at
the one extreme verged on the psychotic, and at the
other extreme merged with affective temperaments.
The diagnostic categories which are established in
this broad spectrum include:
Bipolar I for manic episodes with or without
major depression: the illness can take an extremely psychotic form, including schizobipolar variants.
Bipolar II refers to patients with recurrent major
depressions associated with spontaneous hypomania, and representing the most common phenotype of bipolar disorder; current data indicate that
the modal duration of hypomanic episodes is two
days. Recurrent brief hypomanias, with excitation
as short as one day, when complicated by major
depression, should also be classified as a variant
of bipolar II.
Table 10
The benefits of life charting a
Document prior course
Patient as active partner
Applicability for clinical research
Assess partial treatment

responses
Directs future clinical trials

(sequential trials and rational
polypharmacy)
Uniform, systematic
longitudinal assessments
across patients and sites
Continuity between
retrospective and prospective
assessments
Opportunity for education

Target psychotherapy
Useful for evaluating details

of drug responsiveness
Psychosocial precipitants
Increased compliance
Severity, duration, and

patterning of affective
disturbances are mapped
Seasonal variation
Detection of early warning system
Tolerance patterns
Medicalization of illness
Illness variables quantified

based on daily prospective
ratings
Manic switches or cycle

acceleration (e.g., TCA,
MAOI, SSRI)
Destigmatization
Portable history
Enables consultations
Precise structure of illness

thus available for subsequent
definitions of ill and well
states (arbitrary cutoffs not
needed)
Based on Leverich and Post (1998).
Another variant of the bipolar II pattern can be

termed cyclothymic depression. These are major
depressive episodes superimposed on cyclothymic
mood swings.
As for clinically depressed patients who experience hypomanias during antidepressant treatment (sometimes referred to as bipolar III), the
evidence is nearly unanimous in supporting bipolar status for these patients.
Patients within the spectrum, especially when
recurrence is high and the interepisodic period is not
free of affective manifestations, may meet criteria for
personality disorders. This is particularly true for
bipolar II disorder arising from a cyclothymic
baseline. In view of their extreme mood lability,
especially when pursuing subacute or chronic course,
these patients are often misclassified as borderline
personality disorder. Treatment considerations indicate that in the presence of prominent affective
symptoms of bipolar nature, a bipolar spectrum
diagnosis should have precedence to Axis II personality disorders. Actually, mood lability has been
prospectively validated as a sensitive and specific
predictor of bipolar II outcome.
Rapid-cycling represents a transient phase in the
course of bipolar especially bipolar II disorder,
and occurring in up to 20% of patients. It is distinct
from mixed states, which are presently best characterized as dysphoric-mania. Mixed states occur in
an average of 40% of bipolar patients, and do not
need to have the full constellation of depressive and
manic symptoms; two or more depressive symptoms
appear sufficient in imparting mixed state status to
manic patients.
Alcohol and substance abuse is highly comorbid
across the entire spectrum of bipolar disorders.
Although the present review did not consider with
the requisite depth the differential diagnosis of
bipolar from alcohol and / or substance abuse disorders, the latter have been given an exaggerated
preferential status in DSM-IV. Thus, so-called alcohol- or substance-induced mood disorders should
not be diagnosed before prospective follow-up; it is
not uncommon at all for mood swings to persist
following detoxification, suggesting that these disorders may have much in common with bipolar
spectrum conditions. This is an area of fertile clinical
research in search of investigators with the requisite
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will to measure bipolarity broadly across different

pattens of alcohol and substance use, abuse, and
addiction.
The foregoing conclusions, based on an extensive
literature, challenge several conventions in our formal classificatory system (i.e., ICD-10 and DSM-IV)
regarding duration thresholds and multiple barriers in
the diagnosis of various bipolar subtypes. We submit
that the enlargement of classic bipolar disorders to
include a spectrum of conditions ranging from
psychotic to ambulatory forms will greatly enhance
both clinical practice and research endeavors. Lastly,
some form of life charting of patients course will
further enhance the documentation of the natural
progression of bipolar disorder a colourful
graphic representation of episodes of all severity and
residual or subthreshold symptoms, as well as stressors and treatments provided.
Appendix A. Charting patients course 1
In his pioneering work, Emil Kraepelin (1921)
instituted a systematic and detailed approach to
patient care by recording acutely and longitudinally
each patients manic and depressive episodes using a
life chart graph. This description of the course of
bipolar disorder generated the most comprehensive
and still extraordinarily relevant clinical observations
that continue to have far-reaching implications to
date. Moreover, as documented by Kraepelin, in
some patients the illness can progress from: (1)
isolated, intermittent episodes; (2) to more rapid
recurrences with regular or irregular patterning; (3)
to a pattern of rhythmic, continuous cycling; and, (4)
ultimately, to one of ultradian and chaotic frequencies and patterns (Kramlinger and Post, 1995) as
schematized in Fig. 1 and delineated in Fig. 2.
Life charts make no a priori assumptions about
patients course of illness but collect information
about the retrospective and prospective course of
illness in a systematic and continuous fashion by
using functional impairment as a measure of episode
1
The appendix was kindly provided by Gabrielle S. Leverich,

M.S.W. from the Biological Psychiatry Branch of the National
Institute of Mental Health. It is based on ongoing protocols being
pursued as part of the Stanley Foundation Bipolar program
(Leverich and Post, 1998).
S22
severity that can be corroborated by family members,

friends, diaries, calendars and so on, and are further
validated through pertinent records such as hospital
and physician notes. The NIMH Life Chart Methodology (NIMH-LCME, Leverich and Post, 1998)
thus provides a longitudinal description of the variegated course of bipolar illness and its response to
treatment in the different phases of illness progression.
As illustrated in Fig. 1, retrospective and prospective course of illness is charted with manic episodes
above and depressive episodes below a date line that
also signifies baseline or euthymic mood.
Time domain for retrospective assessment is by
month while the prospective (i.e., current) ratings are
done on a daily basis. Daily prospective ratings are
instituted to promote better monitoring of acute and
longitudinal treatment response and to achieve better
symptom control through dose adjustments and
treatment augmentation.
Assessment of episode severity uses criteria that
are based on the degree of functional incapacitation
arising from mood disturbances. This categorization
of episode severity by functional impairment helps
uncover affective episodes that otherwise might have
been missed. For example, patients might not remember a period of depressed mood but associated
missed days of work or plummeting academic grades
as a result of a mood change will be recalled with
greater certainty and accuracy.
Retrospective life-charting employs three levels
of episode severity as a conservative measure of
retrospective recall. Mild depression indicates a
distinct alteration in mood from normal but is not
associated with functional impairment in the patients usual social or occupational roles. Moderate
depression signifies a distinct increase in mood
symptoms and patients have significant difficulties in
their usual roles but are able to function with extra
effort. In severe depressive episodes the patient is
essentially unable to function outside or inside the
home, requires supportive or protective care, or is
hospitalized. Only depressive episodes of moderate
or greater severity are integrated into a formal
episode count (unless contiguous to a moderate or
severe episode, thereby adding to the duration factor
of that episode); but the recording of mild depression
can contribute to a better estimation of subsyndromal
symptomatology and completeness of remission.
Mild hypomania involves a distinct increase of

energy with either no impairment or an enhanced
ability to function. A period of hypomania in the
mild range only would still be considered and
counted as an episode because of the tendency by the
patient and family to minimize or overlook these
periods. Moderate mania is clearly noticeable to the
patients environment and causes significant disruptions in behavior and productivity of the patient.
Severe mania includes out-of-control activity, bizarre
behaviors, often no sleep for days, and possible
psychosis; the patient is unable to function in any
goal-oriented activities and requires close supervision or hospitalization. A dysphoric, depressive, or
anxious mania at any severity level is denoted by
cross-hatching. Hospitalizations for mania or depression are shaded in for easy recognition of the
patients most difficult phases of illness.
In daily prospective ratings manic and depressive
symptoms of moderate severity are further distinguished. Low moderate signifies functioning with
some difficulty, while high moderate includes much
difficulty in functioning.
Treatments, including medications and psychotherapy, are charted directly above the depressive
and manic ratings (Fig. 1) to better elucidate and
evaluate both acute and longterm responsiveness to
single or multiple treatments and their dose adjustments. This graphic depiction helps elucidate details
of treatment response that is not always obvious
from chart review or office notes.
While life charting facilitates acute and long-term
evaluation of pharmacotherapies, it also allows the
assessment of psychosocial stressors, seasonality,
endocrine determinants such as menarche, childbirth,
menopause, and other potential precipitating factors
such as anniversaries of significant events. Recording
of stressors in the life event section, intercalated
below the depressive phases (Fig. 1), forms the basic
outline of the patients psychosocial history, provides
a useful framework for inquiry about episodes, and
assists in the estimation of the patients stress
reactivity to repeated stressors (i.e., matching events)
and novel occurrences in the longitudinal course of
the illness. An event can be rated for its negative or
positive impact (from 2 4 to 1 4).
Patients are encouraged to begin daily prospective
ratings at the time of first treatment contact, while
they construct their own retrospective life chart in
Fig. 1. Schema for graphing course of affective illness.
S23
S24
Fig. 2. Phases in illness evolution and tretment response in a bipolar II female.
Fig. 3. NIMH 2 LCM prosective self-ratings (My Chart).
S25
S26
more detail when less ill or euthymic to facilitate

recall. Wherever possible, the life chart is reworked
and expanded in collaboration with the clinician as
part of ongoing clinical care and history taking.
Prospective ratings can be accomplished in six
steps:
1. Patients are instructed to first rate their mood on
the mood analogue scale (where 0 is most depressed ever, 50 balanced, and 100 is most
activated or manic ever).
2. Assess how much their mood has affected their
ability to function in their usual daily social and
occupational roles. If rapid and distinct mood
switches occur within a single day (ultradian
cycling), this is depicted graphically as in Fig. 1.
3. Record the number of switches / day as well as the
highest and lowest mood ratings for the day. This
type of rapid, dramatic, and distinct mood fluctuations can be between depression and either
euphoric or dysphoric mania allowing the distinction between ultra-ultra rapid cycling and
dysphoric mania.
4. Hours of sleep of the previous night (daytime
naps are not included) are entered and rounded to
the nearest hour. Menses can be tracked on an
additional date line at the bottom of the rating
form by circling the relevant days for the month.
5. The patient then charts the number of tablets
taken of each medication.
6. Life events (and their impact), severity of side
effects, and other symptoms can then be indicated.
In this fashion, a full daily prospective rating takes
few minutes, and is easy to accomplish after a little
practice. Establishing a nightly routine of ratings
prior to brushing ones teeth or taking ones medications is encouraged. Most patients like the process
and come to greatly value their active participation in
the management of their own illness. The patient can
thus be in possession of his or her life chart as a
portable psychiatric history, which is invaluable in
case of a consultation or transition to a new physician.
Fig. 3 presents a sample rating of a patient (self)
rated prospective NIMH-LCME. The prospective
clinician LCM rating form is similar to the self-rated
version except the 100-mm mood analogue scale and
hours of sleep are omitted and a check box for the

presence of psychosis is included.
In two studies Denicoff et al. (1997, in press)
found preliminary evidence of the reliability and
validity of the prospective life chart technique in that
LCM depression ratings were highly correlated with
Hamilton depression ratings (r 5 0.86), or Inventory
of Depressive Symptomatology (r 5 0.79). LCM
mania ratings were correlated with the Young Mania
Rating Scale (r 5 0.61, r 5 0.66), and both were
highly correlated with the Global Assessment Scale
(r 5 0.81, r 5 0.73).
As in accurate daily monitoring of urine or blood
glucose in diabetes, an accurate life charting of the
illness may lead to the best acute and long-term
treatment decisions, the best chance for minimizing
the impact of the illness on physiology, biochemistry, and behavior, and the most effective approach
for developing optimal treatment paradigms and
algorithms for patients with bipolar illness. The life
chart delineates the diverse and often-times progressive course of the illness, elucidates subcategories
within the illness pattern, and helps address complex
treatment issues (e.g., development of treatment
resistance, cycle acceleration, and possible switches
in polarity). It would appear, therefore, that a careful
longitudinal mapping of the course of illness and
response to treatment is important to the optimal
assessment and treatment of the bipolar patient. Use
of this or related techniques are highly recommended
for detailed tracking of the illness in clinical settings.
Clinicians may wish to adopt a simplified version of
graphing a patients course and treatment modified to their specific clinical setting.
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Journal of Affective Disorders 59 (2000) S5S30

www.elsevier.com / locate / jad

Re-evaluating the prevalence of and diagnostic composition within

Hagop S. Akiskal *, Marc L. Bourgeois , Jules Angst , Robert Post ,

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

(Akiskal, 1983, 1996, 1999), and which embraces a

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

2. Concepts and terminology

which incorporates cyclic depressions, has been

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

depression), type II (depression with hypomania and /

the spectrum and mood-incongruent psychoses

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

Regier et al. (1988) / USA

Emerging new data.

when conforming to narrow definitions of bipolar

Author (year / country)

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

cyclothymia or recurrent hypomania. The increased

that slightly under 10% of a mental health clinics

Summarized from Akiskal et al. (1998).

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

many cyclothymic individuals would also meet

trum of bipolar disorders. Unfortunately, the criteria

Expanded from Akiskal et al. (1977, 1979a,b).

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

Summarized from Angst (1998).

ly indistinguishable from that of bipolar I disorder,

II patients (Cassano et al., 1992). The possible

4.4. The question of axis II

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

toms, the diagnosis of a bipolar spectrum diagnoses

5.1. Clinical diagnosis

reliability of the bipolar II diagnosis was low, all

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

5.2. The specificity of mood lability

TEMPS or Temperament Evaluation of Memphis,

5.3. Clinical prevalence of bipolar II in major

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

1854; Falret, 1854; Kraepelin, 1921) and the current

5.4. The question of pharmacological hypomania

ICD-10 have denied distinct bipolar status to these

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

Summarized from Akiskal et al. (1983).

other anxiety states (reviewed in Himmelhoch, 1998

5.5. Soft bipolarity beyond bipolar II

other conditions, whose link to bipolarity is tenuous

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

return to a less cycling pattern. The higher rates of

7. Bipolar mixed states

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

Koukopoulos and Koukopoulos (1999) have recently

interviews were conducted derived from the DSM-IV

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

prospectively the list of discriminatory depressive

8. Psychotic forms of mania

Based on McElroy et al. (1992), Bauer et al. (1994a,b),

schizobipolar subtype may well represent an even

9. Life charting of patients course

H.S. Akiskal et al. / Journal of Affective Disorders 59 (2000) S5 S30

detailing the course of manic-depressive illness that

challenged the conservative figures of 1% commonly

Patient as active partner